US 20050254058 A1
A method for determining a characteristic of an analyte in a biological sample, the method comprising: directing broadband light by means of a sensing light path at the biological sample, at a target depth defined by the sensing light path and a reference light path; receiving the broadband light reflected from the biological sample by means of the sensing light path; directing the broadband light by means of the reference light path at a fixed reflecting device; and receiving the broadband light reflected from the fixed reflecting device by means of the reference light path. The method also includes interfering the broadband light reflected from the biological sample and the broadband light reflected from the fixed reflecting device; varying an effective light path length of at least one of the reference light path and the sensing light path to define an other target depth; detecting the broadband light resulting from interference of the broadband light reflected from the biological sample and the broadband light reflected from the fixed reflecting device for each of the target depths, to provide an intensity measurement at each of the target depths; and determining the characteristic of the analyte in the biological sample from variations in the intensity measurements.
1. A method for determining a characteristic of an analyte in a biological sample, the method comprising:
directing broadband light by means of a sensing light path at the biological sample, at a target depth defined by said sensing light path and a reference light path;
receiving said broadband light reflected from the biological sample by means of said sensing light path;
directing said broadband light by means of said reference light path at a fixed reflecting device;
receiving said broadband light reflected from said fixed reflecting device by means of said reference light path;
interfering said broadband light reflected from the biological sample and said broadband light reflected from said fixed reflecting device;
varying an effective light path length of at least one of said reference light path and said sensing light path to define an other target depth;
detecting said broadband light resulting from interference of said broadband light reflected from the biological sample and said broadband light reflected from said fixed reflecting device for each of said target depths, to provide an intensity measurement at each of said target depths; and
determining the characteristic of the analyte in the biological sample from variations in said intensity measurements.
2. The method of
modulating an effective light path length of at least one of said reference light path and said sensing light path to enhance interference of said broadband light reflected from the biological sample and said broadband light reflected from said fixed reflecting device, at each of said plurality of target depths.
3. The method of
determining a scattering coefficient from said variations in said intensity measurements; and
determining the characteristic of the analyte in the biological sample from said scattering coefficient.
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12. A system for determining a characteristic of an analyte in a biological sample, the system comprising:
a broadband light source for providing a broadband light;
a sensing light path receptive to said broadband light from said broadband light source, said sensing light path configured to direct said broadband light at the biological sample and to receive said broadband light reflected from the biological sample;
a fixed reflecting device;
a reference light path receptive to said broadband light from said broadband light source, said reference light path configured to direct said broadband light at said fixed reflecting device and to receive said broadband light reflected from said fixed reflecting device, said reference light path coupled with said sensing light path to facilitate interference of said broadband light reflected from the biological sample and said broadband light reflected from said fixed reflecting device, said reference light path and said sensing light path cooperating to define a target depth;
means for varying an effective light path length of at least one of said reference light path and said sensing light path to define an other target depth;
a detector receptive to said broadband light resulting from interference of said broadband light reflected from the biological sample and said broadband light reflected from said fixed reflecting device for each of said target depths, to provide an intensity measurement at each of said target depths; and
processing means configured to determine the characteristic of the analyte in the biological sample from variations in said intensity measurements.
13. The system of
a modulator associated with at least one of said reference light path and said sensing light path a modulator, said modulator for modulating an effective light path length of said least one of said reference light path and said sensing light path to enhance interference of said broadband light reflected from the biological sample and said broadband light reflected from said fixed reflecting device, at each of said plurality of target depths.
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The invention concerns a method for low coherence interferometry of a biological sample using magnitude. The term “biological sample” denotes a body fluid or tissue of an organism. Biological samples are generally optically heterogeneous, that is, they contain a plurality of scattering centers scattering irradiated light. In the case of biological tissue, especially skin tissue, the cell walls and other intra-tissue components form the scattering centers.
Generally, for the qualitative and quantitative analysis in such biological samples, reagents or systems of reagents are used that chemically react with the particular component(s) to be determined. The reaction results in a physically detectable change in the solution of reaction, for instance a change in its color, which can be measured as a measurement quantity. By calibrating with standard samples of known concentration, a correlation is determined between the values of the measurement quantity measured at different concentrations and the particular concentration. These procedures allow accurate and sensitive analyses, but on the other hand they require removing a liquid sample, especially a blood sample, from the body for the analysis (“invasive analysis”).
The American Diabetes Association (ADA) estimates that diabetes afflicts nearly 17 million people in the United States. Diabetes can lead to severe complications over time, including heart failure, kidney failure, blindness, and loss of limb due to poor peripheral circulation. According to ADA, complications arising from diabetes cost the U.S. health care system in excess of $132 Billion.
Diabetes complications are largely due to years of poor blood glucose control. The Diabetes Care and Complications Trial (DCCT) carried out by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) demonstrated that more frequent monitoring of blood glucose and insulin levels can prevent many of the long-term complications of diabetes.
Monitoring of blood glucose concentration is key to managing the therapy of diabetes patients. Monitoring results are used to adjust nutrition, medication, and exercise in order to achieve the best possible glucose control, reducing the complications and mortality associated with diabetes. At present, the most widely used method for monitoring of blood glucose by diabetes patients involves chemical analysis of blood samples taken by puncturing the finger or forearm. This method is painful, requires relatively complex operations, is inconvenient due to disruption of daily life, and may become difficult to perform in the long term due to calluses on the fingers and poor circulation. As a result, the average diabetic patient tests his/her blood glucose levels less than twice a day versus the recommended four or more times per day. Non-invasive blood glucose monitoring techniques with accuracies equal to or better than the current chemical glucose methods are therefore needed.
Accordingly, a number of procedures and apparatus have been suggested to determine glucose in blood, tissue and other biological samples in vivo and in a non-invasive manner. Existing non-invasive procedures for glucose determination include nuclear magnetic resonance (NMR), electron spin resonance (ESR) and infrared spectroscopy. However, none of these procedures have achieved practical significance. Large and costly equipment is required, which are wholly unsuitable for routine analysis or even for patient self-checking (home monitoring).
One of the most promising approaches for non-invasive glucose monitoring is based on optical techniques. Optical glucose monitoring techniques are particularly attractive in that they are relatively fast, use non-ionizing radiation, and generally do not require consumable reagents. Several optical glucose monitoring techniques have been proposed so far, with varying degrees of success. Several of these techniques are discussed herein as background, however, once again, none of these techniques has attained significant commercial success relative to invasive techniques.
One approach is Near-Infrared (NIR)/Mid-Infrared (MIR) spectroscopy. In infrared spectroscopy, radiation from external light sources is transmitted through or reflected by a body part. Spectroscopic techniques are used to analyze the amount of radiation absorbed at each wavelength by the body part constituents and to compare the absorption data to known data for glucose. Practical implementation of a glucose sensor based on these principles is very difficult and several wavelengths are required. Infrared (IR) spectra are sensitive to physical and chemical factors such as temperature, pH, and scattering. Furthermore, spectroscopy is affected by skin pigmentation, use of medications that absorb various IR wavelengths, alterations in blood levels of hemoglobin or other proteins that absorb IR, changes in body temperature, and alterations in the state of hydration or nutrition. In addition, the NIR spectrum of glucose is very similar to that of other sugars, including fructose, which is often used by diabetics. Therefore, the signal (i.e. the change in the absorption spectrum as a function of glucose concentration) is very small compared to noise and to interference resulting especially from the water spectral absorption and other strongly absorbing components.
Another approach is Raman Spectroscopy. With Raman spectroscopy, Raman spectra are observed when incident radiation is inelastically scattered. The loss or gain of photon energy are independent of the excitation frequency and provide specific information about the chemical structure of the sample. The Raman signal is very weak, requiring long data acquisition time, making the device sensitive to light source fluctuations. Measurements are subject to high background noise because of tissue autofluorescence. Scatter and reabsorption in biological tissues make detection of Raman frequency shifts due to physiological concentrations difficult.
Another spectroscopic approach is based on photoacoustics. In photoacoustic spectroscopy, a laser beam pulse is used to rapidly heat the tissue and generate an acoustic pressure wave that can be measured by a microphone or other transducer. The acoustic signal is analyzed to infer blood glucose concentration. Measurements are affected by chemical interferences from biological molecules as well as physical interference from temperature and pressure changes. Current instruments are complex and sensitive to environmental conditions.
Another optical approach considered of glucose monitoring is based on employing polarimetry. Glucose concentration changes the polarization of light fields. The eye's aqueous humor has been suggested as the medium for this technique as skin is not a feasible site due to its high light scattering properties. However, polarization measurements are affected by optical rotation due to cornea, and by other optically active substances. Other interfering factors include saccadic motion and corneal birefringence. In addition, there is a significant lag between blood glucose changes and glucose changes in intra-ocular fluids, of up to 30 minutes.
Yet, another approach employed for glucose monitoring is based on light scattering. Changes in glucose levels induce changes in light scattering properties, generally, of the skin. U.S. Pat. No. 6,226,089 to Hakamata discloses detecting the intensities of backscattering light generated by predetermined interfaces of an eyeball when a laser beam emitted from a semiconductor laser is projected onto the eyeball in a predetermined position. The absorbance or refractive index of the aqueous humor in the anterior chamber of the eyeball is determined on the basis of the intensities of the backscattering light, and the glucose concentration in the aqueous humor is determined on the basis of the absorbance or refractive index in the aqueous humor. Light scattering effects are evident in the near-infrared range, where water absorption is much weaker than at larger wavelengths (medium- and far-infrared). However, techniques that rely on the backscattered light from the aqueous humor of the eye are affected by optical rotation due to cornea, and by other optically active substances. Other interfering factors include saccadic motion and corneal birefringence. Finally, it should be appreciated that there is often a significant time lag, (e.g., up to 30 minutes) between blood glucose changes and glucose changes of the intra-ocular fluids.
Low-Coherence Interferometry (LCI) is one technique for analyzing skin light scattering properties. Low Coherence Interferometry (LCI) is an optical technique that allows for accurate, analysis of the scattering properties of heterogeneous optical media such as biological tissue. In LCI, light from a broad bandwidth light source is first split into sample and reference light beams which are both retro-reflected, from a targeted region of the sample and from a reference mirror, respectively, and are subsequently recombined to generate an interference signal. Constructive interference between the sample and reference beams occurs only if the optical path difference between them is less than the coherence length of the source.
U.S. Pat. No. 5,710,630 to Essenpreis et al. describes a glucose measuring apparatus for the analytical determination of the glucose concentration in a biological sample and comprising a light source to generate the measuring light, light irradiation means comprising a light aperture by means of which the measuring light is irradiated into the biological sample through a boundary surface thereof, a primary-side measuring light path from the light source to the boundary surface, light receiving means for the measuring light emerging from a sample boundary surface following interaction with said sample, and a secondary-side sample light path linking the boundary surface where the measuring light emerges from the sample with a photodetector. The apparatus being characterized in that the light source and the photodetector are connected by a reference light path of defined optical length and in that an optic coupler is inserted into the secondary-side measurement light path which combines the secondary-side measuring light path with the reference light path in such manner that they impinge on the photodetector at the same location thereby generating an interference signal. A glucose concentration is determined utilizing the optical path length of the secondary-side measuring light path inside the sample derived from the interference signal.
The above-discussed and other drawbacks and deficiencies of the prior art are overcome or alleviated by the measurement system and methodology disclosed herein. Disclosed herein in an exemplary embodiment is a method for determining a characteristic of an analyte in a biological sample, the method comprising: directing broadband light by means of a sensing light path at the biological sample, at a target depth defined by the sensing light path and a reference light path; receiving the broadband light reflected from the biological sample by means of the sensing light path; directing the broadband light by means of the reference light path at a fixed reflecting device; and receiving the broadband light reflected from the fixed reflecting device by means of the reference light path. The method also includes interfering the broadband light reflected from the biological sample and the broadband light reflected from the fixed reflecting device; varying an effective light path length of at least one of the reference light path and the sensing light path to define an other target depth; detecting the broadband light resulting from interference of the broadband light reflected from the biological sample and the broadband light reflected from the fixed reflecting device for each of the target depths, to provide an intensity measurement at each of the target depths; and determining the characteristic of the analyte in the biological sample from variations in the intensity measurements.
Disclosed herein in another exemplary embodiment is a system for determining a characteristic of an analyte in a biological sample, the system comprising: a broadband light source for providing a broadband light; and a sensing light path receptive to the broadband light from the broadband light source. The sensing light path is configured to direct the broadband light at the biological sample and to receive the broadband light reflected from the biological sample. The system also comprising: a fixed reflecting device and a reference light path receptive to the broadband light from the broadband light source. The reference light path is configured to direct the broadband light at the fixed reflecting device and to receive the broadband light reflected from the fixed reflecting device. The reference light path is coupled with the sensing light path to facilitate interference of the broadband light reflected from the biological sample and the broadband light reflected from the fixed reflecting device. The reference light path and the sensing light path cooperating to define a target depth. The system further includes a means for varying an effective light path length of at least one of the reference light path and the sensing light path to define an other target depth; a detector receptive to the broadband light resulting from interference of the broadband light reflected from the biological sample and the broadband light reflected from the fixed reflecting device for each of the target depths, to provide an intensity measurement at each of the target depths; and a processing means configured to determine the characteristic of the analyte in the biological sample from variations in the intensity measurements.
These and other features and advantages of the present invention may be best understood by reading the accompanying detailed description of the exemplary embodiments while referring to the accompanying figures wherein like elements are numbered alike in the several figures in which:
Disclosed herein, in several exemplary embodiments are high-sensitivity low coherence interferometric (LCI) systems (instruments) for optical metrology, which in an exemplary embodiment are miniaturized for use in a variety of sensing and monitoring applications, including, but not limited to, trace chemical sensing, optical properties and changes thereof, medical sensing such as non-invasive glucose monitoring and others. In an exemplary embodiment, the instrument is miniaturized, using integrated optics components such as waveguides, splitters and modulators on a single substrate such as, but not limited to, a LiNbO3 (Lithium Niobate) chip. The exemplary embodiments may also involve the use of a “circulator” type of optical component, including of a polarizing beam splitter and quarterwave plate, which can be combined with the light source and detector into a miniature module that prevents optical feedback into the light source while doubling the detected light. Alternatively, instead of the polarizing beam splitter and quarter wave plate one or more isolators and a waveguide coupler may be employed in a similar module to accomplish the same purpose. Disclosed herein in the exemplary embodiments are multiple methodologies and associated systems employed to derive information from the magnitude and/or phase of an interferometric signal.
It will be appreciated that while the exemplary embodiments described herein are suitable for the analysis in comparatively highly scattering, i.e. optically heterogeneous biological samples, optically homogeneous (that is, low-scattering or entirely non-scattering) samples also may be analyzed provided suitable implementations of the embodiments of the invention are employed. It may be further appreciated that the methods discussed herein generally do not allow an absolute measurement of the glucose concentration, but rather a relative measurement from a given baseline. Therefore, calibration to establish a baseline is required. For instance, for one exemplary embodiment, a calibration strip is employed to facilitate calibration. Other methodologies, such as using a sample of known index of refraction, or known glucose concentration may also be employed. The particular glucose concentration in the sample may be determined by any previously known procedure, which allows the determination of the absolute glucose concentration.
It should noted that the light wavelengths discussed below for such methods are in the range of about 300 to about several thousand nanometers (nm), that is in the spectral range from near ultraviolet to near infrared light. In an exemplary embodiment, for the sake of illustration, a wavelength of about 1300 nm is employed. The term “light” as used herein is not to be construed as being limited or restricted to the visible spectral range.
It is well known that the presence of glucose affects the light scattering properties of tissue, and the refractive index denoted as n of the Interstitial Fluid (ISF) and the refractive index of the scattering centers in the tissue-cell membranes, cellular components and protein aggregates. It is also known that a near infrared (NIR) light of a few milliwatts optical power can penetrate the skin harmlessly, whether being delivered directly from the air, a fiber, some appropriate waveguide, or some combination thereof. In the NIR range the refractive index of ISF is about 1.348-1.352, whereas the refractive index of cellular membranes and protein aggregates ranges from about 1.350 to 1.460. Since the tissue under the skin is highly scattering, the light is scattered in all directions, and only a small amount, the so-called ballistic photons, is captured. It is the light from the ballistic photons captured that are employed to produce an interferometric signal. Raising the glucose concentration in the ISF raises the ISF refractive index by approximately 1.52×10−6 per each mg/dl. Furthermore, the physiological delay of blood glucose transfer from blood to the ISF is of the order of only 2-5 minutes, which makes monitoring of blood glucose in ISF highly practical especially compared to existing methodologies that employ the aqueous humor of the eye.
It will also be noted that for a homogeneously scattering medium for which a specific property such as the refractive index is to be measured, it is sufficient to probe at a single depth, as the desired information can be obtained from the phase of the interferometric signal, presumed to be independent of the amplitude. In this case, an instrument as described herein can be configured for measurement at a single depth. However, if desired, to probe for inhomogeneities (local changes of absorption, reflection, or refractive index), the instrument may be configured to measure both the amplitude and the phase of the interferometric signal as functions of depth. Described herein in a first exemplary embodiment is a system configured to probe at a fixed depth, while later embodiments may be employed for measurement at variable depths and for general imaging purposes. In any case, emphasis is placed on miniaturization, portability, low power and low cost.
Finally, it will also be appreciated that while the exemplary embodiments disclosed herein are described with reference and illustration to glucose measurements, applications and implementations for determination of other characteristics of analytes may be understood as being within the scope and breadth of the claims. Furthermore, the methodology and apparatus of several exemplary embodiments are also non-invasive, and thereby eliminate the difficulties associated with existing invasive techniques. In particular, with respect to detection of glucose concentration, the LCI systems of several exemplary embodiments are configured to be non-invasive, avoiding painful lancets and the like.
Another important consideration is that, as a tool, particularly for medical diagnostic applications, the LCI system of the exemplary embodiments is preferably configured to be easily portable, and for use by outpatients it must be small. Once again, for the purpose of illustration, the LCI system 10 will be described in the context of non-invasive glucose monitoring, capable of detecting the glucose concentration in the dermis by just touching the patient's skin with the instrument. Moreover, the LCI system 10 is configured to be readily hand-held to facilitate convenient measurements by a patient without additional assistance in any location.
To facilitate appreciation of the various embodiments of the invention reference may be made to
The splitter-modulator module 40 a includes, but is not limited to, a waveguide input 41, a waveguide output 43, a splitter/coupler 50, and two waveguide light paths: one light path, which is denoted as the reference arm 42, has adjustable length Ir with a reflecting device, hereinafter a mirror 46 at its end; the other light path, which is denoted as the sensing arm 44, allows light to penetrate to a distance z in a medium/object and captures the reflected or scattered light from the medium. It will be appreciated that the captured reflected or scattered light is likely to be only the so-called “ballistic photons”, i.e., those that are along the axis of the waveguide. Provision is also made for one or more modulators 52, 54 in each of the reference arm 42 and sensing arm 44 respectively.
The splitter-modulator module 40 b of this embodiment includes, but is not limited to, a waveguide inputs/output 45, a Y-splitter-combiner 51, and the two waveguide arms: reference arm 42, and sensing arm 44. Once again, provision is also made for one or more modulators 52, 54 in each of the reference arm 42 and sensing arm 44 respectively.
It will be appreciated that while certain components have been described as being in selected modules, e.g., 20, 40, such a configuration is merely illustrative. The various components of the LCI system 10 may readily be distributed in one or more various modules e.g., 20, 40 as suits a given implementation or embodiment. Furthermore, in an exemplary embodiment the waveguide arms 42, 44 and/or fibers 23 are configured for single-transverse-mode transmission, and preferably, but not necessarily, polarization-maintaining waveguides or fibers. Furthermore it will be appreciated that in any of the exemplary embodiments disclosed herein the waveguide and/or fiber tips of each component joined are configured e.g., angled-cleaved in a manner to minimize reflection at the junctions.
In order to perform the prescribed functions and desired processing, as well as the computations therefore (e.g., the computations associated with detecting and utilizing the interference signal, and the like), the LCI system 10, and more particularly, the processing system 60, may include, but is not limited to a computer system including central processing unit (CPU) 62, display 64, storage 66 and the like. The computer system may include, but not be limited to, a processor(s), computer(s), controller(s), memory, storage, register(s), timing, interrupt(s), communication interface(s), and input/output signal interfaces, and the like, as well as combinations comprising at least one of the foregoing. For example, computer system may include signal input/output for controlling and receiving signals from the source-detector module 20 as described herein. Additional features of a computer system and certain processes executed therein may be disclosed at various points herein.
The processing performed throughout the LCI system 10 may be distributed in a variety of manners as will also be described at a later point herein. For example, distributing the processing performed in one ore more modules and among other processors employed. In addition, processes and data may be transmitted via a communications interface, media and the like to other processors for remote processing, additional processing, storage, and database generation. Such distribution may eliminate the need for any such component or process as described or vice versa, combining distributed processes in a various computer systems. Each of the elements described herein may have additional functionality that will be described in more detail herein as well as include functionality and processing ancillary to the disclosed embodiments. As used herein, signal connections may physically take any form capable of transferring a signal, including, but not limited to, electrical, optical, or radio.
The light reflected from the reference mirror 46 (Electric field Er) in the reference arm 42 and the light reflected or scattered from depth z within the biological sample (Electric field Er) in the sensing arm 44 are combined at the optical detector 28, whose output current is proportional the combined electric fields. For example, in one instance, the output of the detector is proportional to the squared magnitude of the total electric field Et=Er+Es.
The detector current Id is given by:
The last term in Equation (1), the interference term, is the quantity of interest denoted as io:
It is convenient to express the interference term io, in terms of the center wavelength λo and the path difference Δl associated with the interferometer, instead of the frequency and time delay. Therefore, using νoλo=c, where c is the speed of light in vacuum, Δν may be written in terms of the wavelength FWHM bandwidth Δλ, to obtain:
A plot of the envelope function G(Δl) and if the interference signal G(Δl)cos φs is shown in
It will be appreciated that the interference signal io exhibits significant amplitude only over a spatial window of approximately twice the coherence length Lc. As the optical bandwidth increases, the coherence length Lc decreases and the spatial measurement window narrows. Thus, LCI provides a means for probing samples at precisely defined locations within the samples.
It is noteworthy to appreciate that the phase, φs, of the interference signal io changes by 2π (from a maximum to a minimum then to another maximum) as Δl varies from 0 to λo. Therefore, a small change in Δl results in a large phase change. It will be further appreciated that the phase of the interference signal io is highly sensitive to small changes of optical properties of the mediums, such as refractive indices, or depth z. Thus, while moderate to large changes may readily be observed by measuring the magnitude of the envelope G(Δl), small changes are best detected by measuring the phase φs of the interference signal io. It will be further appreciated that all the desired information is contained in the range from 0 to 2π. For values of Δl>λo, the interference signal io is repetitive. Thus, the range from 0 to 2π as indicated in
Therefore, it will be readily be appreciated that there are two types of information, which can be derived from the interference signal io: the envelope G(Δl), or its peak G(Δl=0), which may represent scattering, reflection, and absorption; and the more sensitive changes in cos φs due to small optical property changes in the sample. In order to make any such measurements, it is first preferable to separate the DC components Ir and Is from G(Δl) and cos φs in the interferometric signal io described in Equation (5).
In one or more exemplary embodiments of the invention, several methodologies are disclosed for extracting the pertinent magnitude information from the interference signal io described in Equation (5). An exemplary methodology addresses detection of the amplitude/magnitude of the envelope of the interference signal io.
Continuing now with
Using one of the modulators, (m1 52, for example) or an equivalent means, a ramp modulation is applied to one of the interferometer arms, the reference arm 42, for example, changing Ir over a distance from −b to a over a time period T, such that:
The resultant of the modulation represents a sine wave of frequency ƒc with an arbitrary phase φc determined by b, which is amplitude-modulated (AM) by the G(Δl) envelope function, now also a function of time.
It should be noted that it is not essential to scan over as wide a range (e.g., ±2Lc) in order to obtain the peak of the envelope, e.g., G(Δl=0). Advantageously, it is sufficient to ramp over as little as just one wavelength, using a=λo and b=λo/2. The resultant signal is almost a pure sine wave or one that is slightly amplitude-modulated by G(Δl).
Observation of the figures makes it evident that for a=λo there is little need for filtering before peak detection to obtain the amplitude as the ripples in the envelope from peak to peak are quite small. For larger values of a, as depicted for
In an exemplary embodiment, once the magnitude of the interferometric signal io is ascertained, for a selected target depth z, additional LCI signal magnitudes corresponding to other target depths are acquired. Furthermore, if desired, in order to obtain averaged distributions of the LCI signal intensity vs. depth multiple scans corresponding to multiple target depths may be employed. As disclosed herein, there are several methodologies and exemplary LCI systems that may be employed to acquire an interferometric signal io corresponding to selected depths. In one exemplary embodiment, the modulator m1 52 may be employed to add an additional offsets denoted as Δ to the reference arm 42 corresponding to a group of target depth variations Δz in the vicinity of target depth z. This approach is readily implemented employing the LCI system 10 of
To address an example wherein an exemplary embodiment of the invention may be employed for detection and monitoring of glucose concentration, it is well known that the presence of glucose affects the light scattering properties of tissue. An increase of glucose concentration decreases the scattering coefficient of tissue μs. The value of μs depends on the mismatch of the refractive index n of the Interstitial Fluid (ISF) and the refractive index of the scattering centers in the tissue-cell membranes, cellular components and protein aggregates. As stated earlier, raising the glucose concentration in the ISF raises the ISF refractive index by approximately 1.52×10−6 per each mg/dl and thus decreases the refractive index mismatch, leading to a decrease of the scattering coefficient μs.
Turning now to ascertaining a glucose concentration employing magnitudes for an exemplary embodiment, based on a depth profile or depth variations in the vicinity of a target depth z. Based on a single-scattering regime, the Beer-Lambert law may be used to model the attenuation of the light flux through the skin as I(z)=O0 exp(−μtz), where z is the target depth, and μt=μa+μs is the total attenuation coefficient, μa is the absorption coefficient, and μs is the scattering coefficient. Advantageously, for light at 1,300 nm for illustration, μa is negligible, and the total attenuation coefficient μt may readily be approximated as μt≈μs. Therefore it may be seen that the slope of the profile of I(z) may be used to approximate the values of the scattering coefficient μs and therefrom, the glucose concentration. The scattering coefficient is obtained by plotting the LCI amplitude profile on a logarithmic scale and measuring the slope of the logarithmic profile. Changes in the slope of the measured magnitudes/intensities may be recorded in order to monitor scattering coefficient changes, which are related to the index of refraction in the sample and thereby, variations ISF glucose levels. Thus, a glucose concentration may be determined employing as few as two magnitudes corresponding to two target depths or a target depth and a variation in its vicinity. In an exemplary embodiment, a comparison of current measurements for scattering coefficient and/or index of refraction and a baseline measurement based on calibration and/or normalization for a particular patient yields an accurate means of determining the current glucose concentration.
Correlations of glucose concentrations between LCI-based non-invasive measurements employing such methodologies and invasive measurements in the range of about 80-95% can be achieved. It will further be appreciated that when compared to other analytes, glucose, sodium chloride (NaCl), potassium chloride (KCl), and urea produced the highest changes in ISF refractive index, and consequently in scattering coefficient μs with glucose exhibiting the most pronounced effect.
It is well known that the refractive index change Δn in the dermis due to the presence of glucose is ˜1.52×10−6 per milligram per deciliter (mg/dl). Assuming a linear dependence, this gives a glucose concentration C of
With the numbers given above, it will be appreciated that glucose levels from about 0.0026 mg/dl to about 855 mg/dl can be measured at 1-mm probing depth. Similarly, glucose levels from about 0.0013 mg/dl to about 428 mg/dl at 2-mm probing depth. The acceptable glucose concentration in humans ranges from about 70 mg/dl to about 170 mg/dl. Therefore, it is evident that the methodologies disclosed provide a significant benefit when applied particularly to glucose monitoring.
Referring once again to
The structure is called heterostructure because the active and clad layers are made of different material. This is in contrast with ordinary diodes in which the p-n junction is formulated between similar materials of opposite doping. The use of heterostructure has made it possible to confine the electrical carriers to within the active region, thus providing high efficiency and enabling operation at room temperature. In many heterostructures, light is emitted in both TE polarization (the electric field in the plane of the layer) and TM polarization (electric field perpendicular to the layer).
However, useful effects are obtained when the active layer is sufficiently thin such that quantum mechanical effects become manifest. Such thin layers are called “quantum well” (QW) layers. Furthermore, the active layer can be “strained”, i.e., a slight mismatch (of about 1%) with respect to the substrate crystal lattice can be introduced during the deposition of the QW layer. The strain can modify the transition characteristics responsible for light emission in beneficial ways. In particular, the light is completely polarized in the TE mode if the strain is compressive. Thus, it is now possible to make a linear polarized laser or broadband SLD by compressive strain of the active layer. In an exemplary embodiment, such a linearly-polarized light source 22 is employed.
In one exemplary embodiment, as depicted in
In another exemplary embodiment as depicted in
The splitter 25 transmits the horizontally polarized light to the quarter wave plate 26, which coverts the light to another polarization, (for example, circular polarization). Likewise, the returning, circularly polarized light is received by the quarter wave plate 26 and is reconverted to a linear polarization. However, the linear polarization opposite, for example, vertical. The vertically polarized light is transmitted to the polarizing beam splitter 25, which directs all of the light to the detector 28. Advantageously, this approach transmits substantially all of the light i.e., the interference signal, to the detector 28. Whereas embodiments employing the isolator 24 transmits approximately half of the light to the detector 28.
The polarizing beam splitter 25 is a device that transmits light of one polarization (say the horizontal, or TE-polarized SLD light) and reflects at 90° any light of the other polarization (e.g., vertical or TM-polarized). The quarter-wave plate 26 is a device that converts a linearly polarized incident light to circular polarization and converts the reflected circularly-polarized light to a linearly-polarized of the other polarization which is then reflected at a 90° angle by the polarizing beam splitter 25 to the detector 28. Therefore, essentially all the light transmitted by the light source 22 is re-polarized and transmitted to the splitter-modulator module 40 b and all the reflected light from the sample and reflecting device 48 is deflected by the polarizing beam splitter 25 to the detector 28. Advantageously, this doubles the light received at the detector 28 relative to the other embodiments, and at the same time minimizes feedback to the SLD light source 22.
In an exemplary embodiment an SLD chip for the light source 22 has dimensions of approximately 1 mm×0.5 mm×0.1 mm (length×width×thickness), and emits a broadband light typically of up to 50 mW upon the application of an electric current of the order of 200-300 mA. The light is TE-polarized if the active layer is a compressively strained QW. The FWHM spectrum is of the order of 2% to 3% of the central wavelength emission. A SLD light source 22 with 1.3 μm center wavelength emission and operating at 10 mW output power at room temperature would have a bandwidth of about 40 nm and would require about 200 mA of current. In an exemplary embodiment, for continuous wave (cw) operation at room temperature, the SLD light source 22 may be mounted on an optional thermoelectric cooler (TEC) 32 a few millimeters larger than the SLD light source 22 chip to maintain the temperature of the light source 22 within its specified limits. It will be appreciated that the SLD light source 22 and associated TEC 32 peripherals in continuous operation would have the largest power consumption in the LCI system 10. However, without the TEC 32, the SLD junction temperature would rise by several degrees under the applied current and would operate at reduced efficiency.
Advantageously, in yet another exemplary embodiment, the utilization of a TEC 70 may readily be avoided without incurring the effects of significant temperature rise by pulsed operation of the SLD light source 22. Pulsed operation has the further advantage of reducing the SLD electrical power requirement by a factor equal to the pulsing duty cycle. Moreover, for selected applications of digital technology and storage, only a single pulse is sufficient to generate an interference signal and retrieve the desired information. Therefore, for example, with pulses of duration 10 μs and 1% duty factor, the LCI system 10 of an exemplary embodiment can average 1000 measurements per second without causing the SLD light source 22 temperature to rise significantly. Thus, for low power consumption, the LCI system 10 should preferably be designed for the SLD light source 22 to operate in a pulsed mode with a low duty cycle and without a TEC 32. In such a configuration the source-detector module 20 would be on the order of about 2 centimeters (cm)×2 cm×1 cm.
The splitter-modulator module 40 a, and 40 b of an exemplary embodiment includes a splitter/coupler 50 and Y-splitter/combiner 51 respectively, with a “reference” arm 42 and a “sensing” arm 44, the reference arm 42 having a slightly longer optical path (for example, 1 to 3 mm for measurements in biological tissues) than the sensing arm 44. The optical path difference between the two arms 42, 44 is configured such that the LCI system 10 balanced for the chosen probing depth z. Provision is also made to include a modulator m1 52 and m2 54 in the reference arm 42 and sensing arm 44 respectively.
In an exemplary embodiment, the splitter/coupler 50, Y-splitter/combiner 51 reference arm 42 and a sensing arm 44 are formed as waveguides in a substrate. However, other configurations are possible, including but not limited to separate components, waveguides, optical fiber, and the like. The substrate 23 for this module should preferably, but not necessarily, be selected such that the waveguides of the arms 42, 44 and modulators 52, 54 can be fabricated on/in it by standard lithographic and evaporation techniques. In one exemplary embodiment, the waveguides of the arms 42, 44 are fabricated by thermal diffusion of titanium or other suitable metal that increases the index of refraction of the substrate, evaporated through masks of appropriate width for single transverse-mode operation. In another exemplary embodiment, the waveguides are formed by annealed proton exchange in an acid bath. This process raises the refractive index in the diffusion region, thus creating a waveguide by virtue of the refractive index contrast between the diffusion region and the surrounding regions. In an exemplary embodiment, is lithium niobate (LiNbO3) is employed as a substrate 23. It will be appreciated that other possible materials, namely ferroelectric crystals, may be utilized such as lithium tantalite (LiTaO3) and possibly indium phosphide depending on configuration and implementation of the LCI system 10.
Lithium niobate is a ferroelectric crystal material with excellent optical transmission characteristics over a broad wavelength range from the visible to the infrared. It also has a high electro-optic coefficient, i.e., it exhibits a change of refractive index under the application of an external electric field. The refractive index change is proportional to the electric field. The speed of light in a transparent solid is slower than in vacuum because of its refractive index. When light propagates in a waveguide built into the electro-optic material, an applied electric field can alter the delay in the material, and if the electric field is time-varying, this will result in a phase modulation of the light. The LiNbO3 material is very stable, the technology for making it is mature, and LiNbO3 modulators, which can be compact and are commercially available.
In an exemplary embodiment, the high electro-optic coefficient (refractive index change with applied electric field) of lithium niobate is exploited to facilitate implementation of a modulator, such as modulators m1 52 and m2 54. In this embodiment, a modulator is implemented on or about the waveguide arms 42, 44, by depositing metal electrodes 56, 58 in close proximity to the waveguide arms. In one embodiment, the metal electrodes 56, 58 are deposited on the sides of the waveguide arms 42, 44. In another, the metal electrodes 56, 58 may be deposited on the waveguide arms 42, 44 with an appropriate insulation layer, in a selected region.
The refractive index change due to the electro-optic effect is given by
Typical material properties are:
To obtain larger scale modulations, it will be appreciated that an increase in the voltage on/or the length of the modulator will result in larger changes in the index of refraction by the modulator, resulting in an increased variation of the corresponding phase delay. For example, with a configuration of d=10 microns, an applied voltage of only 3.6 volts is sufficient to yield a value of Δl or b (as discussed above) of 1.3 microns (the wavelength of the light discussed in the examples above). This illustrates that a modulator with a range equivalent to the wavelength λ (for example) 1.3 microns may readily be achieved employing the configuration described.
In an exemplary embodiment, the reference arm 42 is terminated in an evaporated mirror (metal or quarter-wave stack) 46, and the sensing arm 44 is terminated in an anti-reflection (AR) coating, or is covered with an index-matching agent 48 that prevents or minimizes reflection from the end of the sensing arm 44 when placed in contact with the object to be measured. In such a configuration splitter-modulator module 40 would be on the order of about 2 cm×2 cm×0.5 cm.
Referring now to
Referring now to
The phase associated with a selected length of the reference arm is pre-calibrated to correspond to a set distance (about 1 to 3 mm) under the skin. The spot size for the light at the tip of the sensing fiber or waveguide of the sensing arm 44 is on the order of a few microns. The LCI system 10 may readily be calibrated by placing a strip of known refractive index (or, in the case of a glucose monitor, known glucose content,) and appropriate thickness at the sensing end of the splitter-modulator module 40 prior to performing a measurement.
The configuration described above with reference to
Referring now to
The disclosed invention can be embodied in the form of computer, controller, or processor implemented processes and apparatuses for practicing those processes. The present invention can also be embodied in the form of computer program code containing instructions embodied in tangible media 66 such as floppy diskettes, CD-ROMs, hard drives, memory chips, or any other computer-readable storage medium, wherein, when the computer program code is loaded into and executed by a computer, controller, or processor 62, the computer, controller, or processor 62 becomes an apparatus for practicing the invention. The present invention may also be embodied in the form of computer program code as a data signal 68 for example, whether stored in a storage medium, loaded into and/or executed by a computer, controller, or processor 62 or transmitted over some transmission medium, such as over electrical wiring or cabling, through fiber optics, or via electromagnetic radiation, wherein, when the computer program code is loaded into and executed by a computer 62, the computer 62 becomes an apparatus for practicing the invention. When implemented on a general-purpose processor the computer program code segments configure the processor to create specific logic circuits.
It will be appreciated that the use of first and second or other similar nomenclature for denoting similar items is not intended to specify or imply any particular order unless otherwise stated.
While the invention has been described with reference to an exemplary embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.